Neuropathic pain (hereinafter referred to as NP) is a kind of chronic pain diseases caused by peripheral nerve and/or central nerve disorder and functional disorder due to cancer or physical injury. Such a pain has lost its original significance of alerting tissue disorder but is no more than a pain. The quality of life (QOL) of a patient is remarkably reduced due to such a pain.
The symptom of NP is, in addition to continuous spontaneous pain, mainly allodynia that a tactile stimulus is felt as a drastic pain. Such a pain is strongly resistant to non-steroidal anti-inflammatory drugs (hereinafter referred to as NSAIDs) such as ibuprofen, and is resistant also to morphine, that is, a narcotic analgesic (Non Patent Document 1).
The pathologic physiology and the cause of NP have not been completely elucidated yet, but the followings have been proved as a result of recent fundamental research:
(1) NP is induced by a damage of peripheral and/or central nerve.
(2) A variety of cytokines and chemokines are released from damaged nerve cells.
(3) The released cytokines and the like cause remarkable activation of microglia known as an immunocompetent cell for the central nerve system.
NP is treated for purposes of relieving the pain, increasing the functional capacity of the patient, and improving his/her activity. For these purposes, for example, administration of an antidepressant, a narcotic analgesic or the like, a nerve block treatment, and an acupuncture and moxibustion treatment are performed. However, any excellent therapeutic method based on the developing mechanism of NP has not been known, and an excellent therapeutic method for NP is desired.
Multiple sclerosis (hereinafter referred to as MS) is a disease that has a focus generated in a central nerve system such as a brain or a spinal cord, and causes various neurological symptoms (such as visual disturbance, dyskinesia, hypesthesia, dysesthesia, pain, dysequilibrium, shivering, dysuria, sexual dysfunction, fatigue, and emotional disorder). MS is divided, depending on the progressive mode of a patient's condition, into a “relapsing-remitting type” wherein relapse and remission are repeated, and a “chronic progressive type” that the symptom is gradually worsened. The chronic progressive type is further divided into a “secondary progressive type” that the relapsing-remitting MS subsequently shows chronic progression, and a “primary progressive type” that obvious relapse does not occur but the symptom is gradually worsened from the initial stage of the onset.
The cause of MS has not been elucidated yet. There is a report about the cause of MS that T cells or macrophages infiltrate into nerve tissues and attack the patient's own myelin covering axon of nerve cells of the brain or the spinal cord, and as a result, inflammation is caused in the myelin and hence demyelination is caused, which leads to MS (Non Patent Document 2)
A therapeutic method for MS is divided into three categories, that is, inhibition of inflammation in an acute period, inhibition of relapse or progression, and relief of the symptoms.
In a treatment in an acute period, glucocorticoid (a steroid anti-inflammatory drug) is used to inhibit the inflammation of a site where the myelin is damaged. MS is a disease difficult to completely recover because relapse and remission repeatedly occur. Various immunological treatments based on the pathogenetic mechanism of MS have been studied (Non Patent Document 2), and it is presumed that interferon β and immunosuppressive agents are effective. However, a sufficiently effective and safe therapeutic method has not been established. In particular, an excellent therapeutic method for MS at the time of relapse is desired.
MIF is a cytokine secreted from activated lymphocytes and having various biological activities. It is known to exhibit activities for, for example, an immune system, an endocrine system, and proliferation and differentiation of cells. Particularly, MIF plays a significant role in systemic inflammation and immune response, and is a factor pertaining also to a delayed hypersensitivity reaction for inhibiting random migration of macrophages. Besides, MIF has dopachrome tautomerase activity (Non Patent Document 3).
On the other hand, MIF is known to have homology to glutathione S-transferase, to show detoxification, to be secreted from adenohypophysis at the time of endotoxic shock, to be induced by a low level of glucocorticoid, and to oppose its immunosuppressive effect (Non Patent Document 4). In other words, MIF inhibits the activity of glucocorticoid, antagonizes the anti-inflammatory effect of endogenous or therapeutically administered glucocorticoid, and works also as a cause or an aggravating factor of an inflammatory disease and an inflammatory state.
Besides, MIF is indispensable for activation of T cells, is expressed in various cells, and is strongly expressed particularly in the nerve system.
In the relation between MIF and diseases, for example, an MIF inhibitor relieves an allodynia symptom of an animal model for NP. On the other hand, a mouse model showing a stimulus sensitivity reaction aggravated by stress can be produced by injecting recombinant MIF to a normal mouse (Non Patent Document 5). Besides, in an animal model for NP, specifically, in a model for the allodynia induced by sciatic nerve ligation, MIF is highly expressed in the ipsilateral dorsal horn of spinal cord, and signaling molecules on the downstream side from MIF are activated (Non Patent Document 6). Furthermore, in an MIF knockout mouse, the allodynia induced by sciatic nerve ligation is eliminated (Non Patent Documents 5 and 6). Accordingly, MIF is presumed to be indispensable for expression of the symptoms of NP.
On the other hand, in an MS patient, the MIF concentration in a cerebrospinal fluid is significantly increased at the time of relapse, when compared to the time of remission (Non Patent Document 7). Besides, experimental autoimmune encephalomyelitis (hereinafter referred to as EAE) of a mouse, that is, a model animal for MS, can be prevented for the relapse by knocking out MIF genes (Non Patent Document 8). It is obvious from these facts that MIF plays an extremely significant role in the formation of NP and MS.
EAE, that is, the animal model for MS, includes a model for reproducing primary onset of an acute period (monophasic) and a model for reproducing chronic relapsing/remitting condition, and in general, rats are used for the former and mice are used for the latter to construct the model.
It is reported, for example, that cyclophosphamide of an immunosuppressive agent inhibits the onset of acute EAE in rats but is ineffective for relapsing type or chronic progressive type of EAE in mice (Non Patent Document 9).
It is also reported that a rat or mouse anti-α4 integrin antibody equivalent to an MS therapeutic agent, natalizumab, delayed the onset and reduced the severity of the disease with respect to the acute EAE in rats, and inhibited the EAE onset in mice by administration for preventing EAE, but the symptoms were aggravated by therapeutic administration (Non Patent Documents 10 and 11).
A benzopyran derivative exhibits an antiarthritic effect (Patent Document 1), an inhibitory effect for production of inflammatory cytokines, such as interleukin-1β and interleukin-6, and an immunomodulatory effect (Non Patent Documents 12, 13 and 14), and is known to be useful for a treatment of rheumatoid arthritis and other arthritis, and autoimmune diseases (Patent Document 2). Besides, it is known to be effective for the acute EAE in rats (Non Patent Document 15).
It is, however, not known at all that the benzopyran derivative binds to MIF to inhibit its biological activities, as mentioned above.
Besides, the effectiveness of the benzopyran derivative for NP as mentioned above is not known at all, and the effectiveness thereof for the relapsing-remitting or secondary progressive MS at the time of relapse is also not known at all.